Loweralkyl-n-(1-loweralkyl-5-nitro-imidazole-2-carbonyl)carbamates

ABSTRACT

N-(1-LOWERALKYL-5-NITROIMIDAZOL-2-YL CARBONYL) UREAS AND CARBAMATES HAVING ANTIPROTOZOAL ACTIVITY PREPARED BY REACTION OF 1-LOWERALKYL-5-NITROIMIDAZOLE-2-CARBOXAMIDE WITH OXALYL HALIDE AND THEN WITH AN APPROPRIATE ALCOHOL OR AMINE. THE PRODUCT COMPOUNDS ARE USEFUL AS PARASITICIDES.

United States Patent Int. Cl. (107:! 49/36 US. Cl. 260-309 3 ClaimsABSTRACT OF THE DISCLOSURE N-(1-loweralkyl-S-nitroimidazol-Z-ylcarbonyl) ureas and carbamates having antiprotozoal activity prepared byreaction of 1-loweralkyl-S-nitroimidazole-Z-carboxamide with oxalylhalide and then with an appropriate alcohol or amine. The productcompounds are useful as parasiticides.

This is a division of United States application Ser. No. 800,705, filedFeb. 19, 1969, now United States Pat. 3,632,817.

BACKGROUND OF THE INVENTION This invention relates generally to newnitroimidazole derivatives, particularly new nitroimidazoloyl urea andcarbamate compounds and to a method for their preparation. In its mostspecific aspects the invention is concerned with novel1-loweralkyl-5-nitroimidazoloyl ureas and lloweralkyl-S-nitroimidazoloylearbamates, with the chemical synthesis of these new heterocycliccompounds, with compositions containing such compounds and with the useof such compounds and compositions as parasiticides.

Histomoniasis is an extremely destructive poultry disease, the causativeorganism being the protozoan parasite H istomonas meleagrzdis. Thisdisease, also known as enterohepatitis or turkey blackhead, is a seriouseconomic problem in the turkey-raising industry. The infestationfrequently spreads rapidly in turkey flocks and high mortality rates dueto the disease are common. The compounds now commercially available fortreating enterohepatitis are somewhat beneficial, but none have provenentirely satisfactory because of the development of resistant strains ofthe causative organism or because undesired side effects are frequentlyobserved at therapeutic dose levels.

The protozoan disease trichomoniasis, caused by T. vaginalis, primarilyinfests the human vagina and is the etiological agent of a verytroublesome and prevalent form of vaginal infestation known as T.vaginalr's vaginitis. Drugs heretofore available for treating thiscondition, like those used for treating enterohepatitis, have certainlimitations and disadvantages.

According to this invention, it has now been found that certain1-loweralkyl-S-nitroimidazolyl ureas and carbamates are highly effectiveparasiticides, especially with regard to the organisms causinghistomoniasis and triehomoniasis. An important feature of the newcompounds of this invention is that the substituent attached to the 2position of the imidazole moiety of the active comounds is a carbonylurea or carbonyl carbamate group. The urea and carbamate moieties may befurther substituted as will be more fully described hereinafter.

A principal object of the present invention is to provide a new class ofchemical compounds which have a high degree of antiprotozoal activity.Another object is to provide new 1-loweralkyl-S-nitroimidazolyl ureasand carbamates. A further object is to provide a process for thepreparation of the novel compounds. Another object is to "ice provideantitrichomonal and antihistomonal compositions contaimng the novelcompounds of this invention as ingredients thereof. Further objects willbecome apparent from the following description of the invention.

The novel 1-loweralkyl-S-nitroimidazoloyl urea and carbamate compoundsof this invention are represented by the structural formula R representsa loweralkyl group of about 1-5 carbon atoms; and X represents CR or NRR wherein R represents a loweral kyl group of about 1-5 carbon atoms, asubstituted loweralkyl group, an aryl group, a

substituted aryl group or a heteroaryl group, R and R independentlyrepresent hydrogen, a loweralkyl group of about 1-5 carbon atoms, asubstituted loweralkyl group, an aryl group or a substituted aryl groupand R and R together with their common nitrogen atom represent aheteroaryl group.

As described above, the term loweralkyl is intended to define an alkylgroup having from about 1 to about 5 carbon atoms, e.g. methyl, ethyl,n-propyl, isopropyl, nbutyl, t-butyl, amyl, isoamyl and the like.

Representative substituents exemplified by R above, include lower alkyl,substituted loweralkyl, e.g. hydroxyethyl, aminomethyl, carboxamidoethyland the like, aryl, e.g. phenyl or naphthyl and the like, substitutedaryl, e.g. cyanophenyl, nitrophenyl, xylyl, tolyl, halophenyl such aschlorophenyl or bromophenyl and alkoxyphenyl such as methoxyphenyl orethoxyphenyl and the like, or heteroaryl, i.e. a 5- or 6-memberednitrogen-containing heterocyclic group characterized by aromaticity,such as thiazolyl, irnidazolyl, pyridyl, pyrimidyl, thienyl and thelike.

Substituents exemplified by R and R above, are hydrogen, lower alkyl offrom about 1 to about 5 carbon atoms, e.g. methyl, ethyl, amyl and thelike, substituted lower alkyl, e.g. hydroxyethyl, haloloweralkyl, e.g.chloroethyl, bromobutyl, cyanoethyl and the like, aryl, e.g. phenyl,naphthyl and the like, substituted aryl, e.g. nitrophenyl, cyanophenyl,alkylphenyl, e.g. tolyl, xylyl, halophenyl, e.g. chlorophenyl,bromophenyl, alkoxyphenyl, e.g. methoxyphenyl, butoxphenyl and the like.

Additionally R and R together with their common nitrogen atom, representa heteroaryl group having 5 or 6 members, e.g. thiazolyl, imidazolyl,pyridyl, pyrimidyl, thienyl, morpholinyl, pyrrolidinyl and the like.

Preferably, R is loweralkyl, R is methyl or ethyl, R and R are eachhydrogen, methyl, hydroxyethyl, phenyl or p-m'trophenyl and R and Rtogether with their common nitrogen atoms, are morpholino.

In accordance with this invention, one method of preparing the novelnitroimidazolyl ureas and carbamates described herein is depicted in thefollowing flow diagram.

wherein Thus, a 1 loweralkyl nitroimidazole 2-carboxamide is treatedwith an equivalent or slight excess of phosgene or oxalyl halide, e.g.oxalyl chloride or oxalyl bromide, in ethylene dichloride or othersuitable nonreactive solvent, e.g. carbon tetrachloride, chloroform,dichloroethane, toluene and the like. The suspension thus obtained isheated at reflux for between /2 and four hours. In this manner, theintermediate 2-carbonyl isocyanate illustrated in the flow diagram isformed. To prep-are the urea and carbamate derivatives of the presentinvention, there is added to the reaction mixture containing the 2-carbonyl isocyanate a compound of the formula HX wherein X is definedabove. Thus HX will be an alcohol or an amine depending on whether thecarbamate or urea derivative is desired.

Particular examples of compounds of the formula HX are ammonia, monoanddialkylamines, e.g. methylamine, diethylamine, p-aminoethanol,l-aminopropanol, aniline, p-nitroaniline, naphthylamine, morpholine,pyridine, ethanol, ethylene glycol and the like.

The l-loweralkyl-S-nitroimidazole-Z-carboxamides employed as startingmaterials in the present invention are prepared according to syntheticmethods known in the art. One method for preparing these compounds isdescribed in U.S. Pat. 3,341,549 whereby a l-loweralkyl-Z-cyano-S-nitroimidazole is contacted with a base, e.g. an aqueoussolution of an alkali metal hydroxide.

The 1-loweralkyl-5-nitroimidazoloyl ureas and carbamates of thisinvention are effective in the control of enterohepatitis in turkeys andin the control of trichomoniasis. In the treatment of enterohepatitis,the compounds are administered to turkeys mixed with an element ofturkey sustenance, e.-g. feed or drinking water. Good control of thedisease is obtained when the compounds of.

this invention are incorporated in a turkey feed ration at levels offrom about 0.001% to about 0.1% by weight of the feed and preferably,from about 0.006% to 0.025% by weight of the feed. The optimumconcentration will depend to a large extent on the age of the birds, theseverity of the infection and the particular compound employed. Withthese feed levels, good control of the disease is obtained with no orminimal growth retardation.

The feed levels at which representative members of the compounds of theinvention are active in controlling enterohepatitis in turkeys are asfollows:

Compound: Percent by weight in feed N-(lmethyl-5-nitroimidazole-2-carbonyl) As previously stated, thel-loweralkyl-S-nitroinfldazoloyl ureas and carbamates described hereinalso have a significant degree of antitrichomonal activity. Whenemployed in treating trichomoniasis, they may be administered orally inunit dosage form, e.g. as tablets or capsules. Such unit dosage formscontaining from about to about 100 mg. of active antitrichomonalingredient'are quite satisfactory and are prepared by techniques knownto those skilled in the pharmaceutical art. Thus, these unit dosageforms will contain the normal diluents, excipients, lubricating agentsand extenders regularly emp y in co pound g uch forms.

Alternatively, the drugs may be suspended or dissolved in liquidvehicles designed for oral administration. The final preparation may bein the form of a solution, emulsion, suspension, syrup or the like andmay be adopted for ultimate use by known techniques.

The compounds of this invention are also useful as topicaltrichomonacides. When employing the compounds in this manner, one ormore of the active agents are uniformly distributed in a suitablechemotherapeutic vehicle that is chemically compatible with theparticular compound selected, noninhibiting with respect to the actionof the effective agent upon T. vaginalis and essentially noninjurioustobody tissue under the conditions of use. Oil and water types ofemulsions or creams as well as aqueous jellies are suitable vehicles.

Representative compounds which are active in controlling trichomoniasisare set forth below. The activity indicated is that displayed in vivo inmice infested with the trichomonal infection. Activity is expressed inmg./-kg. as determined by the method described in Cuckler, Kupferbergand Millman, Chemotherapeutic and Tolerance Studies on Amino-NitroThiazoles, Antibiotics and Chemotherapy, 10, 540-550, 1955.

Also within the purview of this invention are acid addition salts of thenovel compounds described above. The salt may be of an inorganic acidsuch as the hydrochloride, hydrobromide, phosphate, nitrate or sulfateor of an organic acid examples of which are the citrate,

tartrate, adipate, methanesulfonate, p-toluenesulfonate and the like.Non-toxic addition salts, i.e. those tolerated by the host at the doselevels employed, are used when the compounds are to be used in theirsalt form as antiparasitic agents.

The following examples are given for the purpose of illustration and notby way of limitation.

EXAMPLE 1 N-(1-methyl-5-nitroimidazole-2-carbonyl) urea To 10 ml. ofdried ethylene dichloride there is added 500 mg. (0.003 mole) ofl-methyl-S-nitroimidazole-Z- carboxamide. An amount of 0.3 ml. (0.0036mole) of oxalyl chloride is added to the suspension. After refluxing for/2 hour, an additional 10 ml. of ethylene dichloride is added to insurecomplete solution. The solution is then refluxed four hours,concentrated to dryness and the residue is dissolved in 40 ml. ofbenzene. An excess of ammonia is bubbled into the benzene solution toafford N-(l-methyl-S-nitroimidazole-Z-carbonyl) urea as a fine whiteprecipitate, M.P. 190-195 C.

In the same manner as described above, addition of excess monoordi-alkylamine affords the corresponding N -alkyl or N N -dialkyl urea.Thus, excess monomethylamine afiords N -methyl-N-(l-methyl-S-nitroimidazole- 2-carbonyl) urea, M.P. -175" C. and excessdimethylamine affords N ,N -dimethyl-N-(l-methyl-S-nitroimidazole-2-carbonyl) urea, M.P. 129-135 C.

Similarly, addition of excess ethylamine or amylamine affords N -ethyl-N-(l-methyl-5-nitroimidazole 2 carbonyl) urea and N;-amyl-N-(l-rnethyl-5-nitroimidazole- Z-carbonyl) urea, while addition of excessdi-n-propylamine or din-butylamine affords N N -di-n-propyl-N(1-methyl-5-nitroimidazole-2-carbonyl) urea and N N di-n-butyl-N-(l-methyl-S-nitroimidazole 2 carbonyl) urea.

By substituting 1-ethyl-5-nitroimidazole-2-carboxamide,1-propyl-5-nitroimidazole-2-carboxamide,l-butyl-S-nitroimidazole-Z-carboxamide or l-amyl 5 nitroimidazole-Z-carboxamide for l methyl-5-nitroimidazole-2-carboxamide, thel-loweralkyl analogs of the compounds described above are obtained.

EXAMPLE 2 N1- (d-hydroxyethyl) -N l-methyl-5-nitroimidazole-2- carbonylurea A mixture of 170 mg. (0.001 mole) of l-rnethyl-S-nitroimidazole-Z-carboxarnide, 7 ml. of dry ethylene dichloride and 0.1ml. (0.0012 mole) of oxalylbromide is heated at refiux for /2 hour andthe reaction mixture is concentrated to dryness. The dry residue isdissolved in benzene and 0.1 ml. (0.0016 mole) of aminoethanol is addedto afford N -(B-hydroxyethyl)-N -(l-methyl-S- nitroimidazole-Z-carbonyl)urea as a greenish yellow precipitate. After dissolving in alcohol,filtering, washing and drying, the product is obtained as a white,crystalline solid, M.P. 124-128 C.

Substitution of l-ethyl-S-nitroimidazole-Z-carboxamide orl-n-propyl-S-nitroimidazole 2 carboxamide in the above process atfords N-(,8-hydroxyethyl)-N l-ethyl-S- nitroimidazole-2-carbonyl) urea and N-(fi-bydroxyethyn- N -(1-n-propyl-S-nitroimidazole-Z-carbonyl) urea.

Similarly, other N -hydroxyalkyl derivatives are prepared by addition ofthe appropriate aminoalcohol, e.g. l-aminopropanol, l-aminobutanol,l-aminopentanol and the like.

Further, N -haloalkyl and N -cyanoalkyl derivatives are prepared bysubstituting chloroethanol, cyanopropanol and the like for the abovedescribed aminoalcohols.

EXAMPLE 3 N -phenyl-N l-methyl-S-nitroimidazole-Z-carbonyl) urea Amixture of 258 mg. (0.00155 mole) of l-methyl-S-nitroimidazole-Z-carboxamide, 10 ml. of dry ethylene dichloride and 0.16ml. (0.0019 mole) of oxalyl chloride is heated at reflux for one hour.The solution is concentrated to dryness under reduced pressure and thenreconcentrated from a benzene solution. The dry residue is dissolved in50 ml. of benzene and 0.2 m1. (0.0022 mole) of aniline is added. Thereis an immediate separation of solids which are concentrated, filteredand dried to aiford N -phenyl-N -(l-methyl-S-nitroimidazole 2 carbonyl)urea, M.P. 237-238 C.

In the same manner as described above, substitution of p-nitroanilinefor aniline afiords N -p-nitrophenyl-N-(lmethyl-S-nitroimidazole-Z-carbonyl) urea, M.P. 239- 240 C.

Similarly, other N -substituted phenyl compounds are prepared byreacting pcyanoaniline, p-methylaniline, pchloroam'line,p-methoxyaniline and the like in lieu of aniline.

Also, substitution of naphthylamine for aniline in the above processalfords N -naphthyl-N -(l-methyl-S-nitroimidazole-Z-carbonyl) urea.

EXAMPLE 4 N-(N'-morpholinocarbonyl)-l-methyl-5-nitroirnidazole-Z-carboxamide A mixture of 250 mg. (0.0015 mole) of l-methyl-S-nitroimidazole-2-carboxamide, 10 ml. of dry ethylene dichloride and 0.15ml. (0.0018 mole) of oxalyl chloride is refluxed for four hours andallowed to stand overnight at room temperature. The solution isconcentrated to dryness at reduced pressure and then reconcentrated frombenzene. The dry residue is dissolved in 20 ml. of henzene and 0.34 ml.of morpholine is added resulting in a slow separation of solids. Thesolids are filtered, washed and dried to affordN-(N'-morpholinocarbonyl)-1-methyl- 5-nitroimidazole-2-carboxamide as awhite, crystalline solid, M.P. 143-145 C.

Similarly, other N-heteroarylcarbonyl compounds are prepared bysubstituting thiazole, imidazole, pyridine, pyrimidine, thiophene, orpryrrolidine for morpholine in the above procedure.

EXAMPLE 5 Ethyl N-( 1-methyl-S-nitroimidazole-Z-carbonyl) carbamate Amixture of 250 mg. (0.0015 mole)l-methyl-S-nitroimidazole-Z-carboxamide, 10 ml. of dry ethylenedichloride and 0.16 ml. of oxalyl chloride is heated at reflux for onehour. After concentrating the solution to dryness under reduced pressureand reconcentrating from a henzene solution, the residue is dissolved in5 ml. of ethanol and chilled affordingethyl-N-(l-methyl-S-nitroimidazole 2-carbonyl) carbamate, M.P. l27.5-l30C.

Other carbamate derivatives are prepared in the manner described aboveby replacing ethanol with propanol, butanol, ethylene glycol,aminopropanol, carboxarnidoethanol, phenol, naphthol, p-cyanophenol,p-nitrophenol, p-chlorophenol and the like.

PREPARATION 1 1-methyl-5-nitroimidazole-Z-carbonyl isocyanate T 0 10 ml.of dried ethylene dichloride there is added 500 mg. (0.003 mole) of1-methyl-5-nitroimidazole-Z- carboxamide. An amount of 0.3 ml. (0.0036mole) of oxalyl chloride is added to the suspension. After refluxing for/2 hour, an additional 10 ml. of ethylene dichloride is added. Thesolution is then refluxed four hours and the solvent is evaporated atreduced pressure to afford l-rnethyl-S-nitroimidazole-2-carbonylisocyanate as a residue.

Similarly, other l-loweralkyl-5-nitroimidazole-Z-carbonyl isocyanatesare prepared by replacing l-methyl-S- nitroimidazole-Z-carboxamide inthe above procedure with otherl-loweralkyl-S-nitroimidazole-Z-carboxamides.

Obviously, many modifications and variations of the present inventionare possible in the light of the above teachings. It is therefore to beunderstood that, within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described.

What is claimed is:

1. A compound wherein R is loweralkyl of 1-5 carbon atoms, and R isloweralkyl of 1-5 carbon atoms.

2. A compound of claim 1 wherein R is loweralkyl of 1-5 carbon atoms andR is methyl.

3. The compound of claim 2 wherein R is methyl and R is ethyl.

References Cited UNITED STATES PATENTS 3,121,707 2/1964 Anderson et al260-309 3,341,549 9/1967 Henry 260-309 3,458,528 7/1969 Gal 260309 OTHERREFERENCES Basterfield et a1. Chem. Abst., vol. 27, pp. 4222-3 (1933).

Hay et al.: Chem. Abst., vol. 70, No. 47,8181] (1969).

Hoskinson Aust.: J. Chem, vol. 21, pp. 1913-9 (1968).

NATALIE TROUSOF, Primary Examiner

